High Leptin Levels May Protect Against Alzheimer's

by John Gever John Gever,Senior Editor, MedPage Today
December 15, 2009

Action Points

Explain to interested patients that leptin is involved in regulation of appetite and metabolism, but evidence also indicates that it functions more broadly in the central nervous system and elsewhere.

Explain that this study does not have immediate clinical implications. No treatments are available to boost leptin levels artificially, and it is not yet clear that such an approach would prevent or treat Alzheimer's disease.

Framingham Heart Study participants with relatively high leptin levels have developed Alzheimer's disease at much lower rates than those with low levels, researchers found.

After adjusting for known risk factors for Alzheimer's and vascular disease, including body mass index and waist-to-hip ratio, cognitively normal study participants had a hazard ratio of 0.59 of developing Alzheimer's disease later on (95% CI 0.45 to 0.78) for each standard deviation in logarithmically transformed leptin levels, reported Sudha Seshadri, MD, of Boston University, and colleagues.

They also found a hazard ratio for Alzheimer's disease of 0.23 (95% CI 0.08 to 0.61) for individuals in the highest quartile of leptin levels compared with those in the lowest quartile, after adjusting for age, sex, plasma homocysteine, and the apoE epsilon-4 genotype.

"These findings are consistent with recent experimental data indicating that leptin improves memory function in animals through direct effects on the hippocampus and strengthens the evidence that leptin is a hormone with a broad set of actions in the central nervous system," Seshadri and colleagues wrote in the Dec. 16 Journal of the American Medical Association.

"If our findings are confirmed by others, leptin levels in older adults may serve as one of several possible biomarkers for healthy brain aging and, more importantly, may open new pathways for possible preventive and therapeutic intervention."

Leptin was discovered in 1994 by researchers seeking what they believed was a master hormone controlling appetite and body weight, acting in the hypothalamus. Since then, it has been found to have a variety of effects in the body, including activity elsewhere in the central nervous system -- particularly in the hippocampus where it appears to have a role in memory-related processes.

Seshadri and colleagues had an opportunity to examine whether leptin levels are associated with dementia and Alzheimer's disease risk in a large sample with long, high-quality follow-up.

Leptin measurements were available from 785 older Framingham Heart Study participants (mean age 79) with blood samples from 1990 to 1994, who were free of dementia at that time.

Some of these individuals also underwent volumetric brain MRI scans about eight years after the leptin measurements.

Seshadri and colleagues correlated the baseline leptin levels with subsequent development of Alzheimer's disease and all-cause dementia, and also with the volume of various brain regions at the MRI follow-up.

Baseline leptin levels varied substantially: the median in the lowest quartile was 3.6 ng/mL in men and 7.4 ng/mL in women, compared with 14.3 and 38.0 ng/mL, respectively, in the highest quartile.

The apparent protective effect of leptin was somewhat weaker for all-cause dementia.

For example, when the researchers controlled for age, sex, plasma homocysteine, apoE genotype, vascular disease risk factors, and BMI, they found these hazard ratios associated with each standard deviation increase in log-transformed leptin level:

All-cause dementia: 0.75 (95% CI 0.56 to 1.02)

Alzheimer's disease: 0.64 (95% CI 0.46 to 0.89)

Both sets of hazard ratios declined further, and were statistically significant, when the adjustments also included changes in waist-to-hip ratio and baseline scores on a depression assessment.

The MRI data indicated that log-leptin levels were significantly associated with total brain volume as well as the size of the temporal horn -- the latter being inversely related to hippocampal volume.

Total brain volume was significantly related to leptin levels after adjusting for a large number of potential confounders, but the associations with temporal horn volume became insignificant trends when factors in addition to age and sex were included.

"One potential explanation for the stronger association of total cerebral brain volume might be that it is a more robust and reliable measure, with a lower inherent variability when compared with temporal horn volume," Seshadri and colleagues wrote.

Other limitations of the study included the single baseline measurement of leptin and the age and lack of ethnic diversity in the sample.

"Leptin levels were not measured in our participants while they were middle-aged, so we are unable to address the relationship between mid-life leptin and cognitive outcomes," according to the report.

Nevertheless, they noted that their main findings suggest that leptin helps maintain good memory function with age, "a premise that merits further investigation."

They also called for studies to validate leptin as a readily measurable biomarker for Alzheimer's disease risk and progression.

In an accompanying editorial, two independent neurobiology researchers agreed that the latter possibility was intriguing.

"Leading biomarker candidates have focused on the means of detecting abnormal metabolism of beta-amyloid peptides by positron emission tomographic imaging or quantification of a particular beta-amyloid peptide and tau in cerebrospinal fluid; however, it is difficult to imagine that these complex or costly research methods can be adapted as routine for the millions of individuals who need clinical care," wrote Thomas Montine, MD, PhD, of the University of Washington, and Eric Larson, MD, MPH, of Group Health Research Institute, both in Seattle.

They were skeptical that leptin or any other single peripheral biomarker would serve the purpose, but the possibility still provides a rationale for pursuing the role of leptin early in the neurodegeneration process.

"The apparently strong association of high leptin levels with lower risk of Alzheimer disease could provide additional insight into pathways involved in the complex processes affecting late-life neurodegeneration," Montine and Larson wrote.

The study was funded by the National Institutes of Health and several of its individual institutes.

Study authors and the editorialists declared they had no potential conflicts of interest.

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